Is TH p.Ser276Ala (c.826T>G) pathogenic?

TH p.Ser276Ala (c.826T>G) is classified Likely pathogenic in TH (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.492); Very rare (popmax 0.00224%, eas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ser276Ala (c.826T>G)?

TH p.Ser276Ala (c.826T>G) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ser276Ala (c.826T>G) in the general population?

TH p.Ser276Ala (c.826T>G) is very rare (popmax 0.00224%, eas) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TH p.Ser276Ala (c.826T>G)?

AlphaMissense predicts ambiguous (score 0.492) — an in-silico prediction, not a clinical call.

TH p.Ser276Ala

c.826T>G · VCV3767306

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.492	ambiguous
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S307A vs ClinVar S276A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,560 alleles

Overall 0.000125% 2/1,605,212 alleles · very rare exomes 2/1,452,930 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,560
South Asian	0.00112%	89,338

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TH
Protein: p.Ser276Ala
Coding: c.826T>G
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2166902 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 307 UniProt numbering: an α-helix

Full TH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TH-deficient dopa-responsive dystonia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive dopa-responsive dystonia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TH p.Ser276Tyr Likely pathogenic ★★ same residue
TH p.Ser276= Likely benign ★ same residue
TH c.1200+2T>C Likely pathogenic ★★ same condition
TH c.1334+1G>A Likely pathogenic ★★ same condition
TH c.312+1G>A Likely pathogenic ★★ same condition
TH c.488-1G>A Pathogenic ★★ same condition
TH c.644+1G>A Likely pathogenic ★★ same condition
TH c.695+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/th-p-ser276ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown